3-(n-acyl-n-methyl)-amino-1-hydrocarbonsulfonoxy propane compounds and method of preparation



Ser. No. 340,576

3 Claims. (Cl. 260-456) This invention relates to a process for theproduction of SH-dibenzo[ a,d]cycloheptenes. In particular, theinvention relates to the preparation of 5H-dibenzo[a,d] cyclohepteneswhich are substituted at the 5-position with a secondary aminopropyl.More particularly, the invention is concerned with the preparation of5-(3-methylaminopropyl)-5H-dibenzo[a,d] cycloheptene. The invention alsorelates to novel compounds utilized in the process and theirpreparation.

This application is a division of our copending application Serial No.207,405, filed July 3, 1962.

In accordance with the process of the present invention, an alkali metalderivative of 5H-dibenzo[a,d]cycloheptene is reacted with a3-(N-acyl-N-methyl)-amino-1-hydrocarbonsulfonyloxypropane and theresulting 5-[3-(N- acyl Nmethyl)-aminopropyl]-5H-dibenzo[a,d]cycloheptene hydrolyzed to form .thedesired product. This process may be illustrated as follows:

hydrolysis l wherein M represents an alkali metal such as sodium,potassium or lithium; R is a radical selected from the group consistingof hydrogen, alkyl, cycloalkyl, aralkyl and aryl and R is a hydrocarbonradical such as alkyl, cycloalkyl, aralkyl and aryl. The compounds mayalso have substituents on one or both of the benzenoid rings and/ or onthe propyl chain. It will be readily apparent to those skilled in theart that inasmuch as the R and R groups are removed during the process,it is not critical which particular group is utilized to form the3-(N-acyl- N methyl)-amino-1-hydrocarbonsulfonyloxypropane orintermediate acid amide and the choice thereof is subject only to thelimitations of ease of hydrolysis and other practical and economicalconsiderations. However, the preferred groups in each instance are alkyland aryl.

The starting compound, namely, the alkali metal derivative of5H-dibenzo[a,d] cycloheptene may be readily prepared by reacting5H-dibenzo[a,d]cycloheptene with a metalating reagent such as, forexample, sodium amide, potassium amide, phenylsodium, butyllithinm andthe like. The sodium and potassium derivatives may be prepared using theprocess described by Villani, J. Med. and Pharm. Chem. 5, pp. 373-382(1962). Lithium derivative may be prepared in analogous manner usingbutyllithium.

United States Patent 0 3,277,144 Patented Oct. 4, 1966 ice The 3(N-acyl-N-methyl)-amino-1-hydrocarbon-sulfonyloxypropanes may beprepared by reacting 3-methylaminopropanol-l with an acid amide to formthe corresponding 3-(N-acyl-N-methyl)-arninopropanol-1 and thenconverting this to the sulfonyloxy derivatives by treatment with ahydrocarbonsulfonyl halide. This may be illustrated as follows:

wherein X is a halogen, preferably chlorine or bromine and R and R areas previously defined. However, as pointed out hereinabove, although Rand R are preferably alkyl or aryl radicals, it is not critical whichparticular groups, which may be similar or dissimilar, are utilized toform the halide reactant since these groups are subsequently removedduring the process.

The reaction (Step 1) is suitably carried out in the presence of aninert, substantially organic solvent. However, in the case of formamide(i.e., where R=H) which is a liquid or other of the amides which melt atelevated temperatures, a solvent is not necessary since the amide can beutilized as such. The choice of solvent, when employed, is not criticaland a wide variety can be utilized. Representative of these areethyleneglycoldimethylether, diethyleneglycoldimethylether, dioxane andpropyleneglycoldiethylether. The temperature at which the reaction iscarried out is not critical. The reaction may be carried out at elevatedtemperatures and preferably at the reflux temperature of the system.Likewise, the ratio of reactants is not critical and equimolar amountsmay be used although it is preferred to employ an excess of the acidamide. After completion of the reaction, the solvent is removed and thedesired product recovered. Further purification of the product can beachieved by fractional distillation under vacuum.

Conversion (Step 2) of the 3-(N-acyl-N-methyl)-aminopropanol-l to thesulfonyloxypropane derivative is accomplished using an appropriatehydrocarbon sulfonyl 3 halide such as methanesulfonyl chloride,benzenesulfonyl chloride, p-t-oluenesulfonyl chloride, benzylsulfonylchloride and the like. The reaction is suitably carried out in thepresence of an inert, substantially anhydrous organic solvent. Thechoice of solvent is not critical and suitable solvents for the reactioninclude the tertiary amines such as pyridine, dimethylamiline,triethylamine, picoline, quinoline and the like. The temperature atwhich the reaction is carried out is not critical. The reaction may becarried out at room temperature or at elevated temperatures. However, incertain instances the reaction may be highly exothermic and therefore itis desirable to maintain the temperature below about C. Likewise, theratio of reactants is not critical and equimolar amounts may be used. Itis preferred to employ an excess of the tertiary amine. After completionof the reaction, the solvent is removed and the desired productrecovered. Further purification of the product can be achieved byfractional distillation under vacuum.

The reaction between the alkali metal derivative of 5H-dibenzo[a,d]cycloheptene and the 3-(N-acyl-N-methyl)-amino-1-hydrocarbonsulfonyloxypropane is carried out in an inert,substantially anhydrous organic solvent. The choice of solvent is notcritical. Suitable solvents include the aromatic hydrocarbons such asbenzene, toluene and the like; aliphatic hydrocarbons such as heptene,hexane and the like; ethers such as diethylether, diamylether and thelike. Equimolar amounts of reactants are preferably employed and thereaction proceeds at room temperature. However, the temperature is notcritical and elevated temperatures up to the reflux temperature of thesystem may be used. After completion of the reaction, the solvent isremoved and the acid amide derivative recovered. Further purificationcan be achieved by fractional distillation under vacuum.

Conversion to the (3 methylaminopropyl)-5H-dibenzo[a,d]cycloheptene isaccomplished by hydrolyzing the acid amide derivative. While this may becarried out under either acidic or basic conditions, employing alcoholicsolutions of potassium hydroxide, sodium hydroxide, hydrochloric acid,acetic acid and the like as the hydrolyzing medium, the hydrolysis ispreferably conducted under basic conditions.

The end compound, namely, 4-(3-methylarninopropyl)-SH-dibenzo[a,d]cycloheptene, prepared by the process of the presentinvention, is useful in the treatment of mental health conditions as itis an antidepressant and serves as a mood elevator or a psychicenergizer. For this purpose, the daily dosage is within the range of5-250 mg., preferably taken in divided amounts over the day.

The following examples are given for purposes of illustrating thepresent invention and are not to be construed as limiting the invention.

Example 1.Preparation of 3-(N-formyl-N-methyl)- aminopropanol-I Amixture of 40 g. of 3-methylaminopropanol-l and 20 g. of formamide isheated while stirring for 4 hours at 165 C. The crude product isfractionated in vacuo using a Widmer column yielding substantially pure3-(N-formyl- N-methyD-aminopropanol-l.

Example 2 Following the procedure of Example 1 and employing acetamide,propionamide, butyramide, benzamide and phenylacetamide in place offormamide, there is obtained 3-(N-acetyl-N-methyl)-aminopropanol-l,3-(N-propionyl- N methyl) aminopropanol-l, 3-(N-butyryl-N-methyl)-aminopropanol-l, B-(N-benzoyl-N-methyl) aminopropanol-l and3-(N-phenylacetyl-N-m'ethyl)-aminopropanol-1, respectively.

Example 3.Preparati0n of 3-(N-formyl-N-methyl) amino-1 -methanesulfonyloxypropane 1 mole of 3-(N-formyl-N-methyl)-aminopropanol-1 isdissolved in 250 ml. of pyridine. While cooling, 1 mole ofmethanesulfonyl chloride is added slowly with stirring. After standingovernight at room temperature, the mixture is poured onto crushed iceand then extracted with benzene. The benzene solution is washed free ofpyridine with dilute sulfuric acid, then washed neutral with sodiumbicarbonate solution and then with water and dried over magnesiumsulfate. Evaporation of the benzene solution in vacuo yieldssubstantially pure 3-(N-formyl-N-methyl)-amino-1-methanesulfonyloxypropane.

Example 4 Following the procedure of Example 3 and employing3-(N-acetyl-N-methyl)-aminopropanol-1, 3 (N-benzoyl-N-methyl)-aminopropanol-l and 3-(N-phenylaeetyl-N-methyl)-aminopropanol-1 in place of 3-(N-formyl-N-methyl)-aminopropanol-1, there is obtained the correspondingsulfonyloxypropane derivative.

to room temperature and a solution of 0.1 mole of 3-(N- Iformyl-N-methyl) -amino-1-methanesulfonyloxypropane in 100 ml. of etheradded. The mixture is then refluxed with stirring for 5 hours and then100 ml. of water added. The ether layer is then washed with dilutehydrochloric acid, then water and then dried over magnesium sulfate andevaporated to dryness yielding 5-[3-(N-formyl-N- methyl) -aminopropyl]-5H-dibenzo [a,d] cycloheptene.

Example 6 Following the procedure of Example 5 and employing equivalentquantities of 3-(N-acetyl-N-methyl)-amino-1- methanesulfonyloxypropane,3-(N-benzoyl N methyl)- amino-l-methanesulfonyloxypropane and3-(N-phenyla-cetyl-N-methyl)-amino1-methanesulfonyloxypropane in placeof 3-(N-formyl-N-methyl)-amino-1-methanesulfonyloxypropane there isobtained, respectively, 5-[3-N-acetyl- N-methyl)-aminopropyl]-5Hdi-benzo[a,d] cycloheptene, 5-[3-(N-benzoyl-N-methyl)-aminopropyl] 5Hdibenzo [a,d] cycloheptene and 5-[3-(N-phenylacetyl-N-methyl)-aminopropyl] -5H-di'benzo[a,d]cycloheptene.

Example 7.Preparati0n of 5-(3-methylaminopr0pyl)-5H-dibenzo[a,d]cycloheptene from 5-[3(N-f0rmyl-N- methyl) aminopropyl]-5H-dibenz0[a,d] cycloheptene 29.5 g. of5-[3-(N-formyl-Nmethyl)-aminopropyl]- SH-dibenzo[a,dJcycloheptene isrefluxed for 24 hours under nitrogen in a solution of 36.3 g. ofpotassium hydroxide in 378 ml. of n-butanol. After cooling to room tem-I perature, the solvent is evaporated in vacuo, the residue is stirredwith 200 ml. of water, 300 ml. of n-hexane, the layers separated, thewater layer extracted with 100 ml. of n-hexane and the combined hexanelayers washed with water (2 x 100 m1.) and then with 0.5 N sulfuric acid(100 x 80 x 80 ml.). The acid solution is then alkalized and extractedwith ether (2 x 150 m1. and 1 x ml.), dried over MgSO and the solutionevaporated to dryness yielding substantially pure5-(3-rnethylaminopropyl)-5H- dibenzo[ a,d] cycloheptene.

Example 8 Following the procedure of Example 7 and employing equivalentquantities of 5[3-(N-acetyl-N-methyl)-amino-.

propyl]-5H-dibenzo[a,d] cycloheptene, 5-[3 (N-benzoyl- N-methyl)-aminopropyl]-5H-di-benzo[a,d] cycloheptene and5-[3-(N-phenylacetyl-N-methyl) -aminopropyl] 5H-dibenzo[a,d]cycloheptene, there is similarly obtained 5-(3-methylaminopropyl) -5H-dibenzo[ a,d] cyclohep tene.

We claim: 1. A compound of the structural formula wherein R is sydrogen,lower alkyl, phenyl or benzyl and R is lower alkyl, phenyl, tolyl orbenzyl.

2. 3-(N-formyl-N-methyl)-a.mino-1 methanesulfonyloxypropane.

3. A process which comprises reacting 3-methyl-aminopropanol-l with acompound of the structural formula 0 II c 5 6 wherein R is hydrogen,alkyl, cycloalkyl, aralkyl or aryl to References Cited by the Examinerform the corresponding 3-(li-acyl-N-methyl):aminopro- UNITED STATESPATENTS panol-l and then reacting said compound wlth a compound of thestructural formula RSO X, wherein R is 2,816,125 12/1957 Allen et a1260-456 alkyl, cycloalkyl, aralkyl or aryl and X is bromine or 52,825,726 3/1958 Cope etal 260456 chlorine to form a. compound of thestructural formula 3,075,899 1/1963 Strauss et a1 260-456 X OTHERREFERENCES /GH: Wagner et al.: Synthetic Organic Chemistry, pageR'SOBOCHzCHICHIN 0 568 (1953).

\ CHARLES B. PARKER, Primary Examiner.

R JOSEPH P. BRUST, Examiner.

wherein R and are as d fi d FLODY D. HIGEL, Assistant Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3, 277,144 October 4, 1966 Max Tishler et a1 It is hereby certified that errorappears in the above numbered patent requiring correction and that thesaid Letters Patent should read as corrected below.

Column 1, line 45, the left-hand portion of the formula reading line 70,for "(1962) Lithium" read (1962) The lithium column 2, line 5, for"derivatives" read derivative column 4, line 67, for "sydrogen" readhydrogen -D Signed and sealed this 5th day of September 1967.

(SEAL) Attest:

ERNEST W. SWIDER EDWARD J. BRENNER Attesting Officer Commissioner ofPatents

1. A COMPOUND OF THE STRUCTURAL FORMULA